Endocrine Abstracts

Introduction: Alterations of the cAMP signaling pathway are described in adrenal tumors causing Cushing syndrome, specifically mutations in the gene coding for the protein kinase A (PKA) catalytic subunit alpha (PRAKCA) in cortisol producing adenomas (CPA) with overt Cushing syndrome.Materiel and Methods: Eight CPAs without PRKACA mutations were analyzed by whole exome sequencing. Direct sequencing of PRAKCB encoding for the catalytic subunit beta (C&#94...

In a previous study we found mutations in the main catalytic subunit of protein kinase A (PKA Cα) to be responsible for cortisol-secreting adrenocortical adenomas (ACAs). These mutations interfere with the formation of a stable holoenzyme, thus causing constitutive PKA activation. More recently, we identified additional mutations affecting PKA Cα in ACAs associated with overt Cushing syndrome: Ser213Arg_Leu212_Lys214insIle-Ile-Leu-Arg, Cys200_Gly201insVal, Trp197Arg,...

Protein Kinase A (PKA) consists of two catalytic and two regulatory subunits with several isoforms (Cα, β, γ and RIα, IIα, Iβ, IIβ, respectively). Type II regulatory subunits are phosphorylated by PKA in their inhibitory sites, while type I are not. Somatic activating mutations in the gene encoding the catalytic subunit α (Cα) of PKA (PRKACA) have been found in 30–40% of cortisol-producing adrenocortical adenomas (CPA). We rece...

We previously identified mutations in PRKACA, coding for the catalytic a (Ca) subunit of protein kinase A (PKA), as the main genetic alteration in cortisol-producing adrenal adenomas (CPAs) responsible for Cushing’s syndrome. Here, we further investigated the mechanism of action of all PRKACA mutations identified so far by our team (L206R, L199_C200_insW, S213R_L212_K214insIILR, C200_GlyinsV, W197R, del244-248+E249Q and E32V). Five out of seven mutants s...

Previously, we identified seven mutations in the main catalytic subunit of protein kinase A (PKA Cα) to be responsible for cortisol-secreting adrenocortical adenomas (CPAs): L206R, L199_C200_insW, S213R_L212_K214insIILR, C200_GlyinsV, W197R, del244-248+E249Q, E32V. Here we performed a functional characterization of these mutants. Specifically, we evaluated the association between PKA regulatory and catalytic subunits using co-immunoprecipitation and PKA activity using a k...

Protein Kinase A (PKA) consists of two catalytic and two regulatory subunits with several isoforms (Cα,β,γ, RIα,IIα,Iβ,IIβ). In 30–40% of cortisol-producing adrenocortical adenomas (CPA) heterozygous activating somatic mutations in the catalytic subunit α (Cα) of PKA have been found. Previous reports found strikingly reduced levels of RIIβ in CPA compared to other adrenocortical tumors. Here, we investigated the correlatio...

Aldosterone-producing adenomas (APAs) are the most frequent cause of primary aldosteronism (PA). Somatic mutations of KCNJ5, ATP1A1, CACNA1D and ATP2B3 are involved in APAs formation while CTNNB1 and GNAS somatic mutations have been described in both APAs and in cortisol-producing adenomas (CPAs). In contrast, mutations of PRKACA coding for the catalytic subunit of protein kinase A have been yet only identified in ...